Predictive genomic and transgenic analysis of tachykinin gene regulatory systems in the amygdala. (360G-Wellcome-080980_Z_06_Z)

The products of the TAC1 gene, that include the tachykinin substance-P, are expressed in the amygdala where they play an important role in the modulation of fear and anxiety. Understanding the systems that regulate TAC1 expression in the amygdala may provide an important step towards understanding the causes of chronic depression and anxiety that affect 10% of the UK population at some point in their lives. We have used a novel series of post-genomic bioinformatic strategies in combination with transgenic analysis, immunohistochemistry and transgenic organotypic culture to provide evidence that a remote amygdala specific enhancer drives the expression of TAC1 in the amygdala under the influence of the MEIS-1 transcription factor. We will use our unique transgenic lines, that express a marker gene under the influence of ECR1, and the combined skills of all four applicants to examine 1. the DNA-protein interactions, 2. the signal transduction pathways and 3. the ligand receptor interacti ons that make up the regulatory systems that modulate ECR1 activity in the amygdala in both unstressed and mildly stressed transgenic models. Understanding how these regulatory systems operate will facilitate the identification of novel drug targets and the development of more efficacious and specific anti-depressive and anxiolytic therapies.